Inhaled medicines for treating Asthma or Chronic Obstructive Pulmonary Disease, COPD, is preferred than oral dosage form product because they delivers medication directly to the target acting site, hence the given dose is minimized and the systemic side effects are reduced. Most commonly used inhaled medicines include inhaled corticosteroids, beta-2 agonists, anticholinergics, or combinations of the above medicine.
Commercially available inhaled corticosteroid includes Fluticasone propionate, Budesonide, Ciclesonide, Momethasone furoate, Beclomethasone dipropionate, Triamcinolone acetonide, and Tipredane, etc. Due to the anti-inflammatory action, they were used as controller in asthma or COPD treatment either administer alone or combined with long acting beta-2 agonist (LABA).
Commercially available beta-2 agonists include Albuterol sulfate (also called Salbutamol sulphate), Procaterol hydrochloride, Fenoterol hydrocromide, Reproterol hydrochloride, Formoterol, Terbutaline sulphate, and Salmeterol xinafoate.
Both Formoterol and Salmeterol are long acting beta-2 agonists (LABA) with duration of action up to twelve hours. In practice, LABA is suggested to be combined with inhaled corticosteroid and given twice daily to act as controller in patients with moderate to severe Asthma. The reason why LABA is not suggested to be used alone in asthma is that it will develop tolerance through beta-2 receptors down regulation which will results reduced efficacy or even higher exacerbation rate or deaths under routine treatment if used alone. While inhaled corticosteroid could reduce beta-2 receptors' down regulation, consequently reduce the extent of beta-2 agonists' tolerance, hence was suggested to combine with LABA as controller for asthma's long term treatment.
Fenterol, Aalbuterol, Terbutaline, or Procaterol are short acting beta-2 agonist (SABA) with the duration of action between 3 to 6 hours or 4 to 8 hours. In clinical application, SABA is mainly used alone as needed to relieve the status of acute bronchoconstriction, if necessarily, it can be used thrice to four times a day. In the prior art, there are several related patent allocation, such as: 1). the Taiwan application No. 200303767 discloses that the superfine formula of Formoterol contains 0.003-0.192% w/v of (R,R)-(±)-Formoterol fumarate; 2). the Taiwan patent No. 329837 discloses a pharmaceutical composition containing Mometasone furoate for treating airway disease and lung disease; 3). the China application No. CN1305380 discloses a composition including Formoterol and Budesonide for applying on preventing and treating acute asthma; 4). the U.S. Pat. No. 5,972,919 disclose a formulation containing an effective amount Formoterol and Budesonide and the molar ratio of the content is 1:4 to 1:70, 5). the U.S. Pat. Nos. 6,932,962, 6,799,572, 6,638,495, 6,962,151 and U.S. Pat. No. 7,321,059 have disclosed a combination about inhaled corticosteroids, which is one selected from Budesonide, Fluticasone, Mometasone, Beclomethasone, or Ciclesonide, etc. and Beta-2 agonist which is one selected from Fenoterol, Albuterol, Procaterol, Salmeterol, or Formoterol, etc. and 6). the U.S. Pat. Nos. 7,244,742, 7,481,995, and U.S. Pat. No. 6,596,261 further discloses that the compound of inhaled corticosteroids collocating with beta-2 agonists is added to Anticholinergics of Ipratropium. However, what recited in the above-mentioned references are all about techniques of Pharmaceutical formulation, and it is not what disclosed by the present invention that using combinations of acting time, dosage, and usage to improve clinical performances.
Austria et al. disclose that a control therapy by adding low or high dosage of inhaled Budesonides to oral Procaterol for treating patients between 7 to 18 year-old and found under regular asthma treated by Procaterol and Budesonide (Chest, 2005) can improve the asthma condition. However, the numbers of patients are too few, and there is no difference between the low dosage and the high dosage. In addition, on Apr. 4, 2010, Japan disclosed that using 15 to 30 mcg inhaled solution of Procaterol and 250 mcg inhaled suspension of Budesonide on a nebulizer twice a week, after one week, switch to use Budesonide alone for treating regular asthma of teenagers. The above two respiratory therapies are using oral beta-2 agonists to combined with inhaled corticosteroids or using a nebulizer to continuously spray these two medicines, and the above-mentioned respiratory therapies are different from the metered dose inhaled combination product or dry-powder inhalation of the present invention. Furthermore, when the drug delivered through nebulizing solution, patients need to inhale the medicine for a period of 10 to 15 minutes, hence, the drug amount given to the patients are much higher than administered from the metered dose inhaler or the Dry-powder inhaler, and in addition they were all given twice daily as control therapy. Therefore, they are different from the present invention in partial polarity control therapy (eccentric therapy) in order to provide a drug blood concentration variation within a day to meet the need of daily lung function circadian rhythm changes.
Respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD) are caused by urbanization with environmental pollution problems. Such respiratory diseases have become one of the major diseases of globalization. Most research findings show that the high asthma mortality is related to low diagnosis rates and treatment inadequate. In 1993 World Health Organization and the National Institutes of Health invited experts to discuss control solutions of asthma and organized the Global Initiative for Asthma, GINA, which is an ongoing council organization. Every few years, based on medical evidences, the organization constantly updates treatment concepts with new clinical evidences and writes the latest asthma treatment guidelines for national health care information.
Now, GINA treatment guidelines is currently suggesting a step up or step down treatment options based on patient's status of control:                1. Step 1: For most mild asthma patients: Reliever medicine such as rapid short-acting β2-agonists is given as needed for quick relieve of symptoms;        2. Step 2: For mild asthma patients:                    A, controller: a. give low dose inhaled corticosteroids or b. leukotriene inhibitors.            B, reliever: When asthma attack, rapid short-acting β2-agonists was given as needed;                        3. Step 3: For moderate asthma patients:                    A, controller: Selectively give                            a. “low-dose inhaled cortico steroids plus long-acting beta-2 agonists”,                b. medium to high-dose inhaled corticosteroids,                c. “low-dose inhaled corticosteroids plus Leukotriene modifiers”, or                d. “low-dose inhaled cortico steroids plus sustained released theophylline.”                                    B, reliever: When asthma attack, rapid short-acting β2-agonists was given as needed;                        4. Step 4: for severed asthma patients:                    A, controller: to step 3 treatment: select one or more from                            a. “medium to high-dose inhaled corticosteroids plus long-acting beta-2 agonists”,                b. leukotriene modifiers,                c. sustained released theophylline.                                    B, reliever: When asthma attack, rapid short-acting β2-agonists was given as needed;                        5. Step 5. The severe acute-exacerbation:                    A, control treatment: to step 4 treatment add either oral corticosteroids or anti-IgE immunotherapy,            B, reliever: When asthma attack, rapid short-acting β2-agonists was given as needed;                        
From the publications, we know that although beta-2 agonists have a bronchodilating effects, but either short-acting or long-acting beta-2 agonist is not recommended to be used alone to treat patients as controller. The reason was when given higher frequent or higher doses, it will develop acute tolerance (Tachyphylaxis) phenomena, under which, the dose given to the patients need to be increased rapidly to achieve the same therapeutic effect, or sometimes cause the loss of efficacy, or make the patient more vulnerable to asthma attack. Therefore, Tachyphylaxis phenomena might increase the acute exacerbations, hospitalization, and mortality of patients.
Generally it is believed that the acute tolerance of beta2-agonists' result from β2 receptors down regulation under routine beta2-agonist treatment. Besides, it is known that some genotype patients are more vulnerable to develop acute tolerance under beta2-agonist treatment. Nowadays, it is well know that the inhaled corticosteroids can improve the β-2 receptor down regulation phenomenon, and this is why the combination of inhaled corticosteroids and long-acting beta2-agonist given every twelve hours effects is the main current medications for treating Asthma, such as Budesonide plus Formoterol fumarate, Fluticasone propionate plus Salmeterol xinafoate, Fluticasone propionate plus Formoterol fumarate, Ciclesonide plus Formoterol fumarate, Momethasone furoate plus Formoterol fumarate, Beclomethasone plus Formoterol fumarate, or Fluticasone furoate plus Vilanterol trifenatate etc. The dosage form of the above mentioned combination are mainly DPI (Dry Powder Inhaler), or MDI (Metered Dose Inhaler), and such pharmaceutical compositions of these combination have become the main stream of research and development currently.
These combination products contained long acting beta2-agonist and intend to give patients a 24 hours cover of blood concentration, such as Formoterol fumarate and Salmeterol xinafoate, were given twice a day to maintain 24 hours effects, and a 24 hours longer-acting drug Vilanterol trifenatate is given once a day.
Papi, A. et al, in 2007, disclosed a combination composition of Beclomethasone and short-acting agonist, Albuterol, is used for treating mild asthma as controller and it was given twice a day therapy.
In addition to the above-mentioned references, there still are U.S. Pat. Nos. 5,270,305, 5,658,549, 5,674,472, 5,674,860, 6,123,924, 6,143,277, 6,251,368, 6,253,762, 6,315,173, 6,510,969, 6,524,555, 6,546,928, 6,641,800, U.S. Pat. No. RE40045 and U.S. Pat. No. 7,067,502 and U.S. pub. No. 20100008997, No. 20090274771, No. 20090258075, No. 20090047336, No. 20080279788, No. 20080078382, No. 20080066741, No. 20080066739, No. 20070196285, No. 20060054166, No. 20050085445, No. 20040241103, No. 20040105819 and No. 20040101483. Although they disclose many of the “inhaled corticosteroid mixing with beta2-agonist” of the formulation technology or drug delivery technology inventions, but none of them taught about the inhaled corticosteroid mixing with the rapid effects of moderately short-acting beta2-agonist such as Procaterol HCl, etc., and the method of using such combination. 
In U.S. patent database, there are patents disclose the beta2-agonist, Procaterol HCl, used with the inhaled corticosteroid, such as U.S. Pat. Nos. 6,503,537 7,387,794 involving in the preparation of powder of agglomerates; U.S. Pat. Nos. 7,244,414, 7,658,949, 7,687,073, 7,694,676 7,736,628 involving in the dry powder inhaler; U.S. Pat. No. 7,172,752 involving in combination particles; U.S. Pat. No. 7,550,133 related to respiratory drug condensation aerosols; U.S. Pat. No. 7,109,247 for particles dispersions containing nanoparticles; U.S. Pat. No. 6,814,953 related to a nebulized aerosol; U.S. Pat. No. 6,932,962 related to an aerosol drug containing hydrofluoroalkanes and alkyl saccharides, HFA; U.S. Pat. No. 7,244,742 related to adding anti-cholinergic drugs; U.S. Pat. No. 7,267,813 containing crystalline spherical inhalation particles; U.S. Pat. No. 7,459,146 related to using for modified polyethylene glycol, PEG, nanoparticles HFA inhalation aerosol propellants. And what mentioned above is not same as the present invention.
References have also showed that the adding of the inhaled corticosteroid only alleviates part of acute drug tolerance phenomenon of the beta2-agonist. In our research, we also found that when the beta2-agonist was given too high single dose, it will produce an acute drug tolerance. This reveals that there are reasons other than beta2 receptor downregulation to cause the acute tolerance.
According to the relevant references, the mechanism of beta2-agonist's tachyphylaxis may be related to the exhaust of some endogenous trachea-relaxing substances which mediate trachea relaxation. Such as substantially increased intracellular cyclic adenosine monophosphate (cAMP) concentrations after administration of beta2-agonist. The released cAMP is catalyzed by proteases and generates serial reactions to relax the trachea. Therefore, when given a large amount or high frequency of beta2-agonist, the endogenous trachea-relaxing substances will be exhausted simultaneously. When the internal recovery rate of these substances is less than the consumption, it might induce the acute drug tolerance phenomenon.
It is also well know that asthma patient's lung functions will change during a day. Due to the neurohormonal circadian change, the lung function is the worst at 04:00 am and is the best at 16:00 pm. Based on the circadian rhythm of the lung function and the above-mentioned mediating substance exhausted mechanism, the inventor proposed a new way of therapy to asthma or chronic pulmonary obstruction. After carefully testing and research with a spirit of, and a spirit of perseverance, the inventor eventually has proposed an invention, “Inhaled Combination Product for Asthma.” The summary of the present invention is described as follows.